KR930003492B1 - Synthesis of 7-halo-7-deoxylincomycins - Google Patents

Abstract

A process for preparing a 7-halodeoxylincomycin or an analogue thereof, which comprises reacting lincomycin or an analogue thereof with a thionyl halide and dimethylformamide, under mild conditions.

Description

7-halo-7-deoxyrincomycin, clindamycin and methods for preparing analogs thereof

The present invention provides an improved method for preparing pharmaceutically possible forms from 7-halo-7-deoxylin-comycin, including clindamycin, and lincomycin and analogs thereof. It is about. Clindamycin is a well-known antibiotic with pharmaceutically useful properties.

Processes for preparing 7-halo-7-deoxyrincomycin are known. U.S. Patent Nos. 3,435,025, 3,496,163 and 3,509,127 disclose 7-hydroxyl groups of lincomycin and similar compounds by reacting the compound with a Lydon reagent and heating the resulting product, Substituting processes are known. The use of thionyl chloride to convert lincomycin and similar compounds to 7-chloro-7-deoxy compounds is described in US Pat. Nos. 3,496,163, 3,509,127 and 3,574,186. The temperature in the neutral solvent required for the conversion, described in these patents, is considerably higher than room temperature. In this regard, all examples disclose reactions that can be carried out by refluxing in carbon tetrachloride (about 77 ° C.).

A process for preparing 7-halo-7-deoxyrincomycin using sulfite-protected lincomycin and a ridon reagent is described in US Pat. No. 3,714,141.

The use of the Vilsmeier reagent to replace hydroxyl groups with halogen atoms is also described in Angew. Chem. 72, 836 (1960) and Chem. Ber. 96, 2671 (1963). JOC 33, 1074 (1968), published by Evans et al., Used Vilsmeier reagents made from methanesulfonyl chloride and dimethylformamide to successfully replace the first hydroxyl group, but the second hydroxyl group. No attempt was made to substitute.

The structure of the adduct formed between dimethylformamide and thionyl chloride without sulfur dioxide is investigated in the work of Ferre et al. In Tet. Lett.2161 (1969) and the dimethylformamide thionyl chloride adduct Conditions for conversion to the corresponding amide chlorides were found in Chem. Pharm. Bull. 19, 2629 (1971). Helv, the book of all the Bosshard. Chim.Acta. 42, 16153 (1959) disclose the use of dimethylformamide as a catalyst in the conversion of carboxylic acids to acid chlorides.

J. Chem, author of the Hepburn family. Soc. Perkin I, 754 (1976) and Chem. & Ind. 664 (1974) describes the use of amide chlorides obtained from Vilsmeier reagents to replace hydroxyl groups with chlorine or bromine groups. However, compounds containing hydroxyl are relatively simple alcohols and are not as complex as lincomycin molecules.

The use of a mixture of mesyl chloride and N, N-dimethylformamide to replace the first group of hexopyranoxide by chlorine is described in Edwards Tetrahedron Letters, 2369 (1973). have.

Halogenation of nucleosides with amide chlorides is described in Dobs, Tetrahedron Letters, 165 (1969).

Although the prior art describes the use of the Vilsmeier reagent and the amide chloride obtained therefrom under similar reactions to the process reactions of the present invention, the prior art is quite confused. This is particularly true of whether it is desirable to use the Vilsmeier reagent or to remove sulfur dioxide from it, or to use the resulting amide chloride.

However, to the knowledge of the applicant, none of the prior art processes can be carried out under the mild conditions used in the process claimed in the present invention.

7-halo-7-deoxyrincomycin and analogs thereof are prepared by reacting lincomycin with thionyl halide and dimethylformamide. This reaction allows (1) the reaction product between one of lincomycin or an analog thereof and an excess of thionyl halide to react in a solvent consisting essentially of dimethylformamide or (2) lincomycin or one of the analogs And a mixture of and dimethylformamide with a thionyl halide. When selecting (1), the solvent may contain some solvent used for the reaction of lincomycin with thionyl chloride (eg methylene chloride).

The particularly mild reaction conditions associated with the ease of carrying out the reaction and the low energy requirements are one of the process advantages of the present invention. For example, the use of special equipment required for processes performed under more extreme conditions becomes unnecessary.

The order of adding the reactants has been found to be critical for achieving the results of the present invention. Only when the order of addition described in the present invention is used it has been found that useful reaction rates can be reached at temperatures below 40 ° C. Otherwise conditions appear usually for amide chloride or thionyl chloride in an inert solvent process.

When using the route 1 or route 2 of the invention, the reaction is carried out at a temperature of about 0-50 ° C. for about 10-48 hours. Preferred temperatures are about 15-30 ° C. and preferred reaction times are about 1-5 hours.

The reaction is preferably carried out with excess thionyl chloride. As used herein, “excess thionyl halide” means about 4-13 equivalents of halide per equivalent of lincomycin or an analog thereof. The preferred ratio of thionyl halide darcincomycin or analog thereof is about 4-6 equivalents.

Process starting materials are lincomycin or one of its analogs with thionyl halide and dimethylformamide. Lincomycin is a known antibiotic and methods for making it and analogs thereof are well known in the art and described in US Pat. Nos. 3,086,912 and 3,155,580. In addition to those described in the patents cited above, analogs of lincomycin include analogs such as protective lincomycin and matylthiorincosamidide, 3,4-cumyldene-lincomycin and 3,4-benzylidene-lincomycin. US Pat. No. 3,380,992. Lincomycin, lincomycin analog, 7-halo-7-deoxyrincomycin and analogs thereof as used herein refer to free bases or salts thereof. These salts are anhydrides or hydrates.

The following examples of preparations for preparing 7-halo-7-deoxyrincomycin and intermediates useful therein are intended to indicate, but are not intended to limit, the scope of the invention.

Example 1

시간에 걸쳐 반응 온도는 실온까지 증가하고 이때에 29℃까지의 약한 발열이 좀더 많은 기체 발생과 함께 나타난다. 온도는 수조(水槽)에서 25℃까지 조절되고 기체 발생은 중지된다. 이때, 박층 크로마토그래피는 잔류하는 린코마이신이 거의 없는 클린다마이신에 대한 매우 깨끗한 반응을 가리킨다. 수조를 제거하고 반응이 한시간 더(전체 반응 시간은

시간) 진공하에 교반되도록 한다. 산출된 적색 용액을 0℃ 가까이 냉각하고 무수 메탄올(40ml)을 서서히 첨가한다. 배관을 통하여, 반응물을 -10℃ 가까이 냉각된 200g 얼음내의 50% 수산화나트륨 114g으로 냉각시켜, 온도를 37℃이하로 유지시킨다. 냉각의 끝무렵에 50% 수산화나트륨을 추가 사용하여 pH를 11이상으로 유지시킨다. 산출된 혼합물을 45분 동안 37±4℃에서 교반시킨다.Under a nitrogen atmosphere, methylene chloride (53 ml, 1.5 volumes of thionyl chlorides) and thionyl chloride (35 ml, 479 mmoles) are added into an oven dried round bottom flask containing a magnetic stir bar. The resulting solution was cooled in an ice bath and slowly added lincomycin hydrochloride monohydrate [35.0 g, 75.1 mmol, 3.90% water by Kar Fischer titration] over a period of 30 minutes through a solid adder. Add. Residual solid is washed with 4 ml methylene chloride. The resulting mixture is stirred at 0 ° C. for 15 minutes to allow complete dissolution. While cooling with ice-acetone, N, N-dimethylformamide (70 ml, 900 mmol) is added slowly and the temperature is kept below 5 ° C. (about 30 minutes). The cold bath is removed and a house vacuum is applied to the yellow solution. Use dry ice / acetone traps.

Over time, the reaction temperature increases to room temperature, at which time a weak exotherm to 29 ° C. appears with more gas evolution. The temperature is controlled to 25 ° C. in the water bath and gas evolution stops. Thin layer chromatography at this time indicates a very clean reaction to clindamycin with little residual lincomycin. The tank is removed and the reaction

Time) allow to stir under vacuum. The resulting red solution is cooled to near 0 ° C. and anhydrous methanol (40 ml) is added slowly. Through the piping, the reaction is cooled to 114 g of 50% sodium hydroxide in 200 g ice cooled near -10 ° C to maintain the temperature below 37 ° C. At the end of cooling, add 50% sodium hydroxide to maintain the pH above 11. The resulting mixture is stirred at 37 ± 4 ° C. for 45 minutes.

부피가 되도록 농축시킨다. 열음 욕조에서 냉각시키면서, 용액을 농염산으로 pH가 1.5가 되도록 조절하고, 이때 혼합물은 균질하게 된다. 메틸렌 클로라이드(100ml)를 가하면, 상(相)이 분리된다. 유기상은 pH 1.5 수성상(농염상으로 pH 1.5가 되도록 조절된 인산수소칼륨 완충용액)을 통하여 연속적으로(3×150ml) 추출된다. 일부 경계면은 수성상과 함께 유지된다. 각 수성 상은 메틸렌 클로라이드로써 재추출된다(4×150ml). 4개의 모든 수성상은 결합되고, 50% 수산화나트륨으로 pH 10.2가 되도록 조절하고 나서, 농염산으로 pH 8.2가 되도록 조절한다(얼음을 가하여 온도를 25℃ 이하로 유지시킨다). 메틸렌 클로라이드(100ml)를 가하면 상이 분리 된다. 유기상은 pH 6.2(0.5M) 인산염 완충용액으로(2×100ml) 추출한다. pH 8.2와 pH 6.2의 수성 상은 메틸렌 클로라이드로 연속적으로 재추출한다(4×5ml). 합한 유기물은 황산나트륨 상에서 건조시키고 오일로 증발시킨다.The mixture is cooled to room temperature and the pH is adjusted to 7 with concentrated hydrochloric acid. The solution is removed to remove all methanol in vacuo.

Concentrate to volume. While cooling in a hot tub, the solution is adjusted to pH 1.5 with concentrated hydrochloric acid, whereupon the mixture is homogeneous. When methylene chloride (100 ml) is added, the phases are separated. The organic phase is extracted continuously (3 x 150 ml) through a pH 1.5 aqueous phase (potassium hydrogen phosphate buffer adjusted to pH 1.5 as a concentrated salt phase). Some interfaces remain with the aqueous phase. Each aqueous phase is reextracted with methylene chloride (4 x 150 ml). All four aqueous phases are combined and adjusted to pH 10.2 with 50% sodium hydroxide and then to pH 8.2 with concentrated hydrochloric acid (ice is added to keep the temperature below 25 ° C). Methylene chloride (100 ml) is added to separate the phases. The organic phase is extracted with pH 6.2 (0.5 M) phosphate buffer (2 x 100 ml). The aqueous phase at pH 8.2 and pH 6.2 is continuously reextracted with methylene chloride (4 x 5 ml). The combined organics are dried over sodium sulphate and evaporated to oil.

Residual methylene chloride is removed by two ethyl acetate azeotrope mixtures. The oil is dissolved in ethyl acetate (158 ml) and anhydrous ethanol (47 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding the solution with clindamycin hydrochloride ethanol solvate and adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring for one hour at room temperature, the mixture is stirred for 45 minutes at 0 ° C. again, and the slurry is filtered and washed with ethyl acetate. After drying for 3 hours in vacuo, the product reaches 17.04 g, which corresponds to a 68.1% yield of clindamycin hydrochloride ethanol solvate.

Example 2

Lincomycin hydrochloride [35.0 g, 79 mmol, 0.974% water by Karl Fischer titration] and N, N-dimethylformamide into an oven dried round bottom flask containing a magnetic stir bar under nitrogen atmosphere (125 ml) is added. The slurry is cooled to near 0 ° C. and thionyl chloride (35 ml, 474 mmole) is added over an hour. The reaction is complete after two hours at room temperature. After cooling to near 0 ° C., anhydrous methanol (75 ml) is added slowly. The solution is stirred for one hour at room temperature. Through the piping, the reaction is cooled down to -10 ° C with 200 g of ice and 114 g of 50% sodium hydroxide in 200 ml methylene chloride beforehand, and the temperature is kept below 16 ° C. At the end of cooling the pH is maintained at 10.5 with the addition of 50% sodium hydroxide.

부피까지 농축시킨다. 메틸렌 클로라이드(100ml)를 가하고, 얼음욕조에서 냉각시키면서, pH를 농염산으로 1.5%가 되도록 조절한다. 층은 분리시키고 유기상은 pH 1.5의 수성 상(농염산으로 pH 1.5가 되도록 조절된 0.5M 인산수소칼륨)을 통하여 연속적으로 (3×150ml)추출된다. 일부 경계층은 수성상과 함께 유지된다. 각 수성상은 메틸렌 클로라이드로 재추출된다(4×50ml). 마지막으로 두 수성상은 추가(2×100ml) 메틸렌 클로라이드로써 추출된다. 4개의 모든 수성상은 결합되고, pH는 50% 수산화나트륨으로써 10.5까지 조절된다. 용액을 실온으로 유지하는데 얼음이 사용된다.Methylene chloride (100 ml) is added with stirring at pH 10.5 for 3 hours at room temperature. The pH is adjusted to 7 and the reaction is kept at room temperature overnight. Mix the mixture in vacuum

Concentrate to volume. Methylene chloride (100 ml) is added and the pH is adjusted to 1.5% with concentrated hydrochloric acid while cooling in an ice bath. The layers are separated and the organic phase is extracted continuously (3 × 150 ml) through an aqueous phase of pH 1.5 (0.5 M potassium hydrogen phosphate adjusted to pH 1.5 with concentrated hydrochloric acid). Some boundary layers remain with the aqueous phase. Each aqueous phase is reextracted with methylene chloride (4 x 50 ml). Finally both aqueous phases are extracted with additional (2 × 100 ml) methylene chloride. All four aqueous phases are combined and the pH is adjusted to 10.5 with 50% sodium hydroxide. Ice is used to keep the solution at room temperature.

The phases are separated by the addition of methylene chloride (100 ml). The organic phase is extracted (2 x 130 ml) through pH 6.2 phosphate buffer (0.5 M). The pH 10.5 and two pH 6.2 aqueous phases are reextracted with methylene chloride (4 x 50 ml). The organics are dried over sodium sulfate and concentrated to an oil in vacuo. Residual methylene chloride is removed by two ethyl acetate azeotrope. The oil is dissolved in ethyl acetate (157 ml) and anhydrous ethanol solvent compound (45 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding the solution with clindamycin hydrochloride ethanol solvate and adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring for one hour at room temperature, the mixture is stirred for 45 minutes at 0 ° C., and the slurry is filtered and washed with ethanol acetate. After the filter cake is dried under vacuum for one hour, 26.65 g (66.5% yield) of clindamycin hydrochloride ethanol solvate is recovered. Clindamycin hydrochloride hydrate is recovered from the ethanol solvent compound by conventional methods.

Example 3

Methylene chloride (12.5 ml, 1.5 volumes of thionyl chloride) and thionyl chloride (8.25 ml, 113 mmol) are added into an oven dried round bottom flask containing a magnetic stir bar under a nitrogen atmosphere. The solution is cooled in an ice bath and lincomycin hydrochloride (10 g, 22.6 mmol, 0.974 wt% water by Kahl Fischer titration) is added slowly through the solid addition apparatus over 25 minutes. The resulting pale pink mixture is stirred at 0 ° C. until homogeneous (15 min). Lithium chloride (LiCl) (4.8 g, 113 mmol, dried at 130 ° C. and 2 mm Hg for 7 hours) is added. While cooling with ice-acetone, N, N-dimethylformamide (17.6 ml, 226 mmole) is added slowly and the temperature is kept below 5 ° C. Remove the cold bath and apply house change. Within 20 minutes the reaction mixture becomes a gel.

시간후에, 반응은 박층 크로마토그래피에 의해서 완료되고, 메틸렌 클로라이드(40ml)를 가하고, 반응을 0℃ 가까이 냉각시킨다. 배관을 통하여, 반응을 50% 수산화나트륨 27.2g과 -10℃ 가까이 냉각된 100g 얼음속으로 냉각시키고, 온도를 20℃ 이하로 유지시킨다. 냉각의 끝무렵에, 50% 수산화나트륨을 추가로 사용하여 pH를 11이상으로 유지시킨다. pH 10-11과 실온에서 2시간동안 교반한 후에, pH를 농염산으로써 7이 되도록 조절하고 혼합물을 실온에서 밤새 유지시킨다.Dimethylformamide (10 ml) is added to facilitate stirring.

After time, the reaction is completed by thin layer chromatography, methylene chloride (40 ml) is added and the reaction is cooled to near 0 ° C. Through the piping, the reaction is cooled into 27.2 g of 50% sodium hydroxide and 100 g ice cooled to near -10 ° C and the temperature is kept below 20 ° C. At the end of cooling, an additional 50% sodium hydroxide is used to maintain the pH above 11. After stirring for 2 hours at pH 10-11 and room temperature, the pH is adjusted to 7 with concentrated hydrochloric acid and the mixture is kept at room temperature overnight.

The pH is readjusted to 10% with 50% sodium hydroxide and the layers are separated. The organic phase is extracted continuously (4 × 75 ml) through an aqueous phase at pH 1.5 (0.5 M potassium hydrogen phosphate adjusted to pH 1.5 with concentrated hydrochloric acid). The aqueous phase at pH 10 is reextracted from methylene chloride (4 x 50 ml) and washed sequentially through each of four pH 1.5 phases. Combine the aqueous phases and adjust the pH to 10.5 with 50% sodium hydroxide. Methylene chloride (100 ml) is added to separate the layers.

시간 동안 건조시킨 후에 생성물은 8.25g에 달하게 되는데 이는 클린다마이신 히드로클로라이드 에탄올 용매화합물의 72% 수율에 해당하게 된다.The organic phase is extracted continuously (2 × 75 ml) through phosphate buffer at pH 6.2 ± 0.1 (0.5 mol). The aqueous phase, pH 10.5 and two pH 6.2, is reextracted with methylene chloride (4 x 50 ml). The organics are dried over sodium sulphate and evaporated to oil. Residual methylene chloride is removed with two ethyl acetate azeotrope. The residual oil is dissolved in ethyl acetate (25 ml) and stirred with activated carbon (0.5 g DARCO Grade G-60) for 45 minutes at room temperature. After filtration through celite 545, the filtrate is evaporated to dryness. The resulting oil is dissolved in ethyl acetate (45 ml) and absolute ethanol (12.9 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding this solution with clindamycin hydrochloride ethanol solvate and adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring for 1 hour at room temperature, the mixture is further stirred at 0 ° C. for 30 minutes, and the slurry is filtered and washed with room temperature ethyl acetate. Under vacuum

After drying over time, the product reaches 8.25 g, corresponding to 72% yield of clindamycin hydrochloride ethanol solvate.

Claims (7)

Under mild conditions, a group consisting of 7-halo-7-deoxyrincomycin and its analogs, consisting of reacting thionyl halide and dimethylformamide with a compound selected from the group consisting of lincomycin and its analogs Method for preparing the selected compound. The process according to claim 1, wherein the reaction product between thionyl halide and a compound selected from the group consisting of lincomycin and its analogs is reacted with dimethylformamide. The process of claim 2 wherein the reaction product of lincomycin with an excess of thionyl chloride is reacted with dimethylformamide to produce clindamycin and any salts thereof. The solvent / reagent system of claim 3, wherein the lincomycin hydrochloride is reacted at less than 50 ° C. with thionyl chloride 4-13 equivalents and the product obtained therefrom is a solvent / reagent system consisting of 0-50 ° C., substantially consisting of dimethylformamide. Reacting c) mycin with any clindamycin hydrochloride. The process according to claim 1, wherein a mixture of dimethylformamide and a compound selected from the group consisting of lincomycin and its analogs is reacted with an excess of thionyl halide. 4. The process according to claim 3, wherein the mixture of lincomycin and dimethylformamide is reacted with an excess of thionyl chloride to prepare clindamycin and any salts thereof. The process of claim 6, wherein the mixture of lincomycin hydrochloride and dimethylformamide is treated with 4-13 equivalents of thionyl chloride and reacted at 0-50 ° C. to produce clindamycin and any clindamycin hydrochloride.